Anacetrapib (chemically named (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[[2-(4-fluoro-2-methoxy-5-propan-2-ylphenyl)-5-(trifluoromethyl)phenyl]methyl]-4-methyl-1,3-oxazolidin-2-one) having the structural formula
has been shown to act as an inhibitor of cholesteryl ester transfer protein (CETP). The complex molecular structure of anacetrapib comprises four cycles A, B, C and D as shown above, wherein this structure can be built up in various manners. The following linear (A+B+C+D) and convergent approach (AB+CD) for the synthesis of anacetrapib have been disclosed in patent applications WO 2006/014413 and WO 2007/005572, respectively. In the preferred embodiments of both aforementioned approaches, the compounds shown in Scheme 1 wherefrom cycle moieties C and D derive, are used as the starting material
wherein substituents Y and Z represent groups suitable for biaryl coupling, and W is a group which is CH2Q or a group which can be converted to CH2Q, in which Q is halo, hydroxy, substituted hydroxy, amino or substituted amino for the direct coupling to another molecule such as a multicycle molecule comprising cycles A and B.
In WO 2006/014413 and WO 2007/005572, 1-halo-4-fluoro-5-isopropyl-2-methoxybenzene as shown in Scheme 2 (XMIP, wherein X is bromo or iodo) is used as the common key intermediate for coupling of fragment D.

The convergent synthesis described in WO 2007/005572 in which biaryl derivative is prepared from 1-(2-fluoro-4-methoxyphenyl)ethanone (compound 1 in Scheme 3) requires a three-step process to obtain 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (compound 5 in Scheme 3) as show in Scheme 3 and appears to be the most favorable approach.

However, the methods described in the aforementioned patent applications have some drawbacks regarding impurity profile, yields and the use of genotoxic solvents. It has been surprisingly found that the method described in WO 2007/005572 leads to an impure final product, which is hard to purify to a pharmaceutical grade by conventional purification methods. Our careful analysis discovered an impurity desmethylanacetrapib (DMAP), a compound having the structural formula
wherein DMAP differs from anacetrapib in that cycle D is substituted with an ethyl moiety (indicated with a circle) instead of an isopropyl moiety.
As shown in Scheme 4, desmethylanacetrapib (DMAP) originates from a very early step of the synthesis described in WO 2007/005572.
wherein 1-ethyl-2-fluoro-4-methoxybenzene (MET) is a result of incompleteness of Grignard methylation of 1-(2-fluoro-4-methoxyphenyl)ethanone (FMAP) due to enolization with the Grignard reagent of the acetophenone FMAP from which the remaining starting material 1-(2-fluoro-4-methoxyphenyl)ethanone (FMAP) is recovered after isolation which is then converted to 1-ethyl-2-fluoro-4-methoxybenzene (MET) in the consecutive step (Scheme 5). Furthermore, when reproducing the prior art process it was observed that approximately 5-10% of FMAP remains in the reaction process and that the impurity MET formed can not be removed in the following steps. Moreover, MET is first transformed to 1-bromo-5-ethyl-4-fluoro-2-methoxybenzene (BrMET) and then to chloro biaryl impurity 2′-(chloromethyl)-5-ethyl-4-fluoro-2-methoxy-4′-(trifluoromethyl)biphenyl (EBFCI) in the consecutive steps, which after coupling with heterocyclic intermediate results in the additional impurity desmethylanacetrapib (DMAP) in the final product anacetrapib.

In order to overcome the above described problem, it was suggested to use anhydrous cerium (III) chloride, which is highly hydroscopic and thus not feasible and/or economical for the usage in industrial scale. Furthermore, while repeating this process, the reaction is too slow and not complete.
Another synthesis described in WO 2007/136672 starts from 1-bromo-2,4-difluorobenzene (compound 1 in Scheme 6) and requires a four-step process to obtain 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (compound 5 in Scheme 6) as shown in Scheme 6.

The critical step of grignardation is performed on the corresponding bromo derivative, what can have some advantages in view of desmethyl impurities. However, the propanol derivative BrFMOL (compound 4 in Scheme 6) cannot be simply hydrogenated to isopropyl derivative BrMIP (compound 5 in Scheme 6) due to considerable debromination to MIP (Scheme 7).

Consequently, said conversion should be performed using tetramethyldisiloxane (TMDSO), which is less suitable reagent for industrial use. Additionally, applying TMDSO leads to modest yields and the formation of siloxane impurities that are difficult to remove. Further drawbacks of the whole synthetic scheme of WO 2007/136672 are the use of dichloroethane as a solvent, since dichloroethane is reasonably anticipated to be human carcinogen, and the use of uneconomical ruthenium catalysts.
Therefore, there is an unmet need for a preparation of highly pure intermediates for the synthesis of cholesterylester transfer protein (CETP) inhibitors such as anacetrapib.